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INSULIN-GLUCAGON-GI PEPTIDES-DIABETES MELLITUS |
Induces a Maturity-Onset Diabetes of the Young (MODY)3-Like Phenotype in Transgenic Mice
Division of Clinical Biochemistry, Department of Internal Medicine (K.A.H.-J., H.W., A.G., H.I., C.B.W.), and Department of Morphology ( P.L.H.), University Medical Center, 1211 Geneva 4, Switzerland
Address all correspondence and requests for reprints to: Claes B. Wollheim, Division of Clinical Biochemistry, Department of Internal Medicine, University Medical Center, 1 rue Michel-Servet, 1211 Geneva 4, Switzerland. E-mail: claes.wollheim{at}medecine.unige.ch
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Abstract |
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 Top Abstract IntroductionMaterials and MethodsResultsDiscussionReferences |
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(HNF-1) cause maturity-onset diabetes of the young
3, a severe form of diabetes characterized by pancreatic
ß-cell dysfunction. We have used targeted expression of a
dominant-negative mutant of HNF-1 to specifically suppress HNF-1
function in ß-cells of transgenic mice. We show that males expressing
the mutant protein became overtly diabetic within 6 wk of age, whereas
females displayed glucose intolerance. Transgenic males exhibited
impaired glucose-stimulated insulin secretion, detected both in
vivo and in the perfused pancreas. Pancreatic insulin content
was markedly decreased in diabetic animals, whereas the glucagon
content was increased. Postnatal islet development was altered, with an
increased -cell to ß-cell ratio. ß-Cell ultrastructure showed
signs of severe ß-cell damage, including mitochondrial swelling. This
animal model of maturity-onset diabetes of the young 3 should be useful
for the further elucidation of the mechanism by which HNF-1
deficiency causes ß-cell dysfunction in this disease. |
Introduction |
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TopAbstractIntroductionMaterials and MethodsResultsDiscussionReferences |
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Mutations in the gene coding for the transcription factor hepatocyte
nuclear factor-1 (HNF-1) cause MODY3. The HNF-1 protein is
composed of three functional domains: a short myosin-like
amino-terminal dimerization domain, an atypical homeobox DNA-binding
domain, and a carboxyl-terminal transactivation domain. Dimerization of
HNF-1 is essential for DNA binding. Patient mutations in any of
these domains could lead to diminished amounts of functional HNF-1
by either a haploinsufficiency or a dominant-negative
mechanism.
HNF-1 was originally characterized as a transcription factor
involved in the control of expression of a wide variety of
liver-specific genes (5), and has more recently been shown
to be an essential transcriptional regulator of bile acid and high
density lipoprotein cholesterol metabolism (6).
However, HNF-1 is also expressed in the kidney, intestine, spleen,
and the exocrine and endocrine pancreas (7). Notably,
HNF-1 has been shown to regulate genes expressed in the
pancreatic ß-cell, such as glucose transporter 2 (Glut-2) and
L-type pyruvate kinase (7, 8, 9, 10, 11). HNF-1
has also been proposed to transactivate the rat insulin I
gene (8, 9, 12). Targeted disruption of the
hnf-1 gene in mice indeed results in elevated plasma
glucose levels, in addition to hepatomegaly and renal dysfunction
(13, 14). However, the pleiotropic effects of the
HNF-1-knockout complicate the analysis of the precise role of
HNF-1 in determining normal pancreatic ß-cell function. The
specific mechanisms by which mutations in HNF-1 cause MODY3 thus
remain unclear.
In this study, we specifically suppressed HNF-1 function in the
ß-cells of transgenic mice. This was achieved by ß-cell-targeted
overexpression of a dominant-negative mutant of rat HNF-1
(DNHNF-1). We have previously shown that DNHNF-1, which lacks DNA
binding activity, exerts its dominant-negative effect by
heterodimerizing with endogenous HNF-1, thus preventing it from
binding to DNA (8). Controlled overexpression of
DNHNF-1 in rat insulinoma cells affects insulin gene transcription
and metabolism secretion coupling (8). Here we show that
transgenic mice expressing DNHNF-1 in pancreatic ß-cells develop
either glucose intolerance or overt diabetes.
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Materials and Methods |
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TopAbstractIntroductionMaterials and MethodsResultsDiscussionReferences |
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transgene was
constructed by inserting the DNHNF-1 cDNA (8) into a
plasmid under the control of the RIP (15), between the
rabbit ß-globin intron and polyadenylation site. The transgene
fragment was excised from the plasmid vector by enzymatic digestion,
separated by gel electrophoresis, and purified on an anion exchange
column (NACS-52 PREPAC columns, obtained from Life Technologies, Inc., Rockville, MD). Transgenic mice were produced by pronuclear microinjection of B6/CBAJ-F1 x B6/CBAJ-F1 zygotes as described (16). DNA solutions were at about 5 ng/µl in a 0.1 mM EDTA-containing buffer. Founder animals were identified by PCR on genomic DNA extracted from tail biopsies (DNeasy tissue kit, QIAGEN AG, Basel, Switzerland). The PCR profile was a standard cycle, repeated 30 times, with 5% DMSO: 94 C for 30 sec, 52 or 47 C for 30 sec, and 68 C for 1 min and 30 sec. The primers (purchased from Microsynth GmbH, Balgach, Switzerland) were: 5', sense primer, 5'-CTGCTAACCATGTTCATGCCT-3'; 3', reverse primer, 5'-TGAATTGCTGAGCCACCTCTC-3' (annealing at 52 C, 770-bp fragment).
Animals were housed in the conventional area of the animal facility of the University of Geneva School of Medicine.
Perfusions
Pancreas perfusions were performed in anesthetized mice as
described (17), with a 1.5 ml/min perfusion rate. Released
insulin in the effluent was measured by a RIA (8).
Glucose tolerance and insulin release tests
Overnight (15 h)-fasted mice were injected ip with glucose (2
g/kg body wt). Whole blood was collected from the tail vein at 0, 30,
60, 90, and 120 min (for glucose tolerance tests) or at 0 and 15/30 min
(for insulin release studies). Blood glucose was measured using a
Medisense (Abbott, Baar, Switzerland) Precision QID
sensor. Plasma insulin was measured using an ultrasensitive rat insulin
ELISA (Mercodia AB, Uppsala, Sweden).
Pancreatic glucagon and insulin content
Dorsal pancreas pieces frozen in liquid nitrogen were
pulverized, resuspended in cold acid ethanol (8), and left
at 4 C for 48 h, with sonication every 24 h. Insulin content
in the acid ethanol supernatant was determined with a rat insulin ELISA
(Mercodia AB). Glucagon content in the same extract was measured by RIA
(Linco Research, Inc., St. Charles, MO).
Histological analysis: optical and electron microscopy and
immunohistochemistry
The animals were killed by cervical dislocation. Dissected
pancreas pieces were either fixed in 4% formalin or 2.5%
glutaraldehyde and embedded in paraffin or epon 812, respectively. For
cryostat sections, tissues were frozen in methylbutane/liquid nitrogen
and stored at -80 C; in some cases, they were fixed in 4%
paraformaldehyde and equilibrated in 30% sucrose before freezing. For
electron microscopy, tissues fixed in glutaraldehyde were postfixed
with OsO4 before embedding in epon 812. Sections
were incubated with a diluted primary antibody for 2 hr at room
temperature, and with an appropriate fluorescein
isothiocyanate-conjugated anti-IgG serum for 1 hr. Guinea pig
antiporcine insulin was used at 1:400, rabbit antiporcine glucagon at
1:400, rabbit antirat HNF-1 (obtained from Dr. R. Cortese, Instituto
di Richerche de Biologia Molecolare P. Angeletti, Rome, Italy) at
1:200, and rabbit antimouse Glut-2 (obtained from Dr. B. Thorens,
Institute of Pharmacology and Toxicology, University of Lausanne,
Lausanne, Switzerland) at 1:200. All dilutions were in PBS
containing 0.1% (wt/vol) sodium azide and 0.5% BSA. For anti-HNF-1
staining, the signal was amplified by incubation for 1 hr with a
biotin-conjugated antirabbit IgG secondary antibody (Jackson ImmunoResearch Laboratories, Inc., West Grove, PA) and for 1 hr
with an ALEXA-conjugated streptavidin complex (Molecular Probes, Inc., Eugene, OR). The anti-HNF-1 antibody was raised against
the N terminus of the protein and hence recognizes both endogenous
HNF-1 and DNHNF-1. Sections were counterstained with 0.001%
(wt/vol) Evans blue before examination in a Carl Zeiss
(Oberkochen, Germany) Axiophot epi-fluorescence microscope.
Ultrastructural analyses were done by using standard copper grids in a JEOL JEM-100CX electron microscope (JEOL GmbH, Eching, Germany). Ultrathin sections were double stained with uranyl acetate and Reynold’s lead citrate. At least two sections from each of a total of three transgenic and three control mice were analyzed.
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Results |
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TopAbstractIntroductionMaterials and MethodsResultsDiscussionReferences |
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induces diabetes or
glucose intolerance in pancreatic ß-cells, we placed the
DNHNF-1 transgene under the transcriptional control of the RIP II
(RIP-DNHNF-1 mice). Six RIP-DNHNF-1 founder mice were obtained.
One female founder became severely diabetic and had no offspring,
whereas the transgenic offspring of two other founders died around 3–4
d after birth of severe hyperglycemia. Hence, 3 RIP-DNHNF-1
transgenic families could be established, 2 of which exhibited no
detectable phenotype. Monitoring of fasting blood glucose in the third
family, however, showed that transgenic males became markedly diabetic
around 6 wk of age (Fig. 1A
). Although
transgenic females remained normoglycemic (at least up to the age of 15
months), an ip glucose tolerance test on 3-month-old females showed
that they were glucose intolerant (Fig. 1B). Females also exhibited
elevated nonfasting blood glucose values at weaning (134% of controls,
P < 0.001) similar to males [138% of controls,
P < 0.001 (Fig. 1C)].
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indicated clear overexpression of DNHNF-1 in
the ß-cell nuclei of 6-wk-old transgenic males (Fig. 1D
, panel b). It
is noteworthy that a similar overexpression was seen in the ß-cells
of the normoglycemic RIP-DNHNF-1 females (Fig. 1D, panel c). In each
case, consecutive sections were stained with an antibody against
insulin (not shown). RT-PCR on total newborn pancreas RNA also
confirmed that the DNHNF-1 message was expressed in the transgenic
animals (not shown). Thus, suppression of HNF-1 function in the
ß-cell induces diabetes in male and glucose intolerance in female
mice.
DNHNF-1 expression affects pancreatic insulin and glucagon
contents
We next determined by immunohistochemistry whether DNHNF-1
expression affects islet structure. Staining of pancreas sections from
RIP-DNHNF-1 mice with an antibody against insulin showed that, at
birth, there was no apparent difference in the number and the
organization of ß-cells between transgenic and control mice (Fig. 2, A and B). However, at 3 wk (the age of
weaning), the islets of the transgenic mice started to become
disorganized, with fewer ß-cells and heterogeneous insulin
immunostaining. This was seen in males (Fig. 2, C and D) as well as in
females (Fig. 2, E and F), and was consistent with the elevated
nonfasting blood glucose observed in these animals (cf. Fig. 1C). At 10 wk of age, the islets of transgenic RIP-DNHNF-1 males had
a clearly reduced number of ß-cells compared with wild-type
littermates (Fig. 2, G and H). The islets of the transgenic males were
moreover disorganized, with an apparently higher number of -cells
scattered throughout the islet instead of their normal peripheral
localization (Fig. 2, I and J).
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males and females. The results presented in Table 1 show that at 3 wk, pancreatic insulin
content in transgenic males and females was 42.9 and 35.5% of control,
respectively. Subsequently, whereas insulin content in females
increased (54.4 and 59.3% of control at 6 and 10 wk, respectively),
the insulin content in males continued to decline (31.1% of control at
6 wk) until reaching a mere 21.1% of control at 10 wk. This decrease
in insulin content contrasted with the 2.2-fold increase in pancreatic
glucagon content observed in 10-wk-old RIP-DNHNF-1 males compared
with controls (Table 1).
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function
in ß-cells leads to a decrease of both pancreatic insulin content and
ß-cell number.
DNHNF-1 expression inhibits insulin secretion
To see whether expression of DNHNF-1 in ß-cells leads to a
specific insulin secretion defect, we perfused the pancreas of 5-wk-old
RIP-DNHNF-1 males (before the onset of diabetes). The insulin
secretion profiles of transgenic and control mice are shown in Fig. 3A. The perfusion protocol included a
15-min stimulation with 16.7 mM glucose, directly followed
by a 16.7 mM glucose plus 20 mM arginine
challenge. To calculate the insulin secreted (the area under the
curve), we further subdivided the secretory responses into a glucose
"first phase," a glucose "second phase," and an "arginine
response" (Fig. 3A). The results show that the first phase of
glucose-stimulated insulin secretion was diminished in transgenic
RIP-DNHNF-1 males (51.3% of control), whereas the second phase was
less affected (69.4% of control). The insulin secretory response to
arginine in the presence of high glucose was even more reduced [26.9%
of control (Fig. 3B)].
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, 5-wk-old
RIP-DNHNF-1 males exhibited a marked inhibition of insulin secretion
(1.8-fold induction at 15 min vs. 2.6-fold in controls),
similar to what was observed in the perfused pancreas. When the
experiment was performed at 6 wk, i.e. the age of onset
of hyperglycemia, the ability of RIP-DNHNF-1 males to secrete
insulin in response to glucose was completely abolished (Fig. 3C, right
panel). Measuring plasma insulin 30 min after the glucose challenge
probably contributed to exaggerate the complete blunting of the
secretory response. The latter still contrasted with the 2.1-fold
increase in secretion seen in control animals.
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males. This secretory defect is detectable
already before the onset of hyperglycemia and worsens with time.
Effects of DNHNF-1 on Glut-2 expression and ß-cell
ultrastructure
Glut-2 is one of the target genes of HNF-1 in ß-cells
(8, 9, 10, 11). We therefore performed immunostaining with an
antibody against Glut-2 and found that the sugar carrier was severely
down-regulated in the islets of 6-wk-old RIP-DNHNF-1 males (Fig. 4, A–C). The down-regulation of Glut-2
cannot be secondary to a prolonged exposure to hyperglycemia, because
at 6 wk, the mice just start to become diabetic.
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males,
we then examined the ultrastructure of islet cells by electron
microscopy (Fig. 5). Already at low
magnification, it was evident that most ß-cells of 6-wk-old
transgenic males exhibited marked vacuolization (compare Fig. 5, B with
A). ß-Cells of RIP-DNHNF-1 males were also shown to contain less
mature secretory granules (compare Fig. 5, D–F, with C). Moreover,
they displayed specific ultrastructural lesions: ß-cell mitochondria
were swollen, as shown in Fig. 5, D and F, contrasting with the intact
organelles seen in a neighboring -cell (Fig. 5F) or in control
ß-cells (Fig. 5C). In addition, most transgenic ß-cells appeared
highly disorganized, with dilated rough endoplasmic reticulum cisternae
(Fig. 5E). Together, these alterations suggest that ß-cell death is
increased in the islets of transgenic mice. This process is not a
typical apoptosis, because no apoptotic bodies nor chromatin
condensation were ever observed. |
Discussion |
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TopAbstractIntroductionMaterials and MethodsResultsDiscussionReferences |
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, the patients do not show signs of altered function of
these organs that could explain the etiology of the disease
(21). In contrast, HNF-1-knockout mice, while being
diabetic, suffer from multiple organ manifestations such as renal
dysfunction with massive glucosuria, pathological liver tests, and
hepatomegaly (13, 14). Although the HNF-1-knockout mice
have yielded important information (6, 11, 13, 22, 23),
the pleiotropic impact of the disruption of the HNF-1 gene
complicates their use for the study of glucose homeostasis.
The transgenic mice with ß-cell-specific suppression of HNF-1
function described in this study phenotypically resemble MODY3
diabetics and carriers. Indeed, expression of DNHNF-1 in the
ß-cells of RIP-DNHNF-1 males results in overt diabetes, whereas it
only causes impaired glucose tolerance in transgenic females. The
severity of the syndrome was paralleled by changes in islet morphology
and hormone content. RIP-DNHNF-1 females exhibited a much milder
phenotype than the males, although they showed the same hyperglycemia
and reduction in pancreatic insulin content at weaning. The subsequent
partial recovery of pancreatic insulin content occurred despite similar
DNHNF-1 expression levels in both sexes. The hormonal profile of the
females probably explains this protection from diabetes, as reported in
other studies (24, 25). This also indicates that the
phenotype of the RIP-DNHNF-1 males cannot be explained by a
nonspecific effect of DNHNF-1 overexpression.
HNF-1 has been shown to control insulin gene transcription in rat
insulinoma cell lines (8, 9). In RIP-DNHNF-1 males,
there was a gradual decrease in pancreatic insulin content, also seen
by immunohistochemistry as an apparent decrease in the number of
ß-cells and heterogeneous insulin staining. Ultrastructural analysis
confirmed the immunohistochemical observations, showing that most
ß-cells in RIP-DNHNF-1 males exhibited a decrease in the number of
mature secretory granules. Reduced expression of other HNF-1 target
genes, including Glut-2, probably contributes to the decreased number
of insulin-positive cells seen at 10 wk. The Glut-2-knockout mouse
indeed displays a decrease in ß-cell mass (26). In
RIP-DNHNF-1 males, there was also a progressive disorganization of
the islets, with an augmented ratio of -cells to ß-cells. This
islet disorganization could be due, at least in part, to the
down-regulation of the cell adhesion molecule E-cadherin observed in a
similar mouse model (27). The increased -cell to
ß-cell ratio was paralleled by an enhanced pancreatic glucagon
content, which could contribute to aggravate the diabetic phenotype. It
is of interest in this context that the normal suppression of glucagon
secretion during a hyperglycemic clamp is impaired in MODY3 patients
(3).
Glucose-stimulated insulin secretion was impaired in
RIP-DNHNF-1 males both in vivo and ex vivo.
Pancreas perfusions revealed that, as in MODY3 patients (2, 3), the first phase of the secretory response to glucose was
attenuated. The response to the combination of arginine and glucose was
also markedly inhibited. These results are similar to published
data on diabetic HNF-1-knockout mice, which exhibit a pronounced
suppression of glucose- and arginine-evoked insulin secretion
(22). It is of interest that Glut-2-knockout mice, like
RIP-DNHNF-1 males, display a specific loss of the first phase of
glucose-induced insulin secretion (26). However,
down-regulation of Glut-2 in the ß-cells of RIP-DNHNF-1 males is
apparently not sufficient to explain the secretory defect because the
glyceraldehyde-evoked response is preserved in Glut-2- but not in
HNF-1-knockout mice. The secretory defect observed in RIP-DNHNF-1
males can already be detected in prediabetic animals, whether assessed
in vivo or ex vivo. At the age of onset of
diabetes, the in vivo insulin secretory response is
completely abolished. Interestingly, this inhibition is more drastic
than could be expected from the 70% decrease in pancreatic insulin
content observed in these animals. As it is generally assumed that 10%
of residual pancreatic insulin content/ß cell mass is enough to
maintain euglycemia (28), these results suggest that
additional mechanisms could account for the impaired
glucose-induced insulin secretion in RIP-DNHNF-1 males.
Electron microscopy studies indeed revealed ultrastructural lesions in
most ß-cells of RIP-DNHNF-1 males. Variable degrees of cell damage
could be observed, such as prominent disorganization of the rough
endoplasmic reticulum appearing as dilated cisternae,
mitochondrial swelling, and reduced numbers of fully mature secretory
granules. Some cells were clearly dying, exhibiting general
vacuolization, but neither apoptotic bodies nor chromatin condensation
were ever observed in the damaged ß-cells of RIP-DNHNF-1 males.
Interestingly, it has been reported before that ß-cell death can
occur without characteristic features of apoptosis (29).
Moreover, it has been shown that cellular ATP is needed for a cell to
undergo classical apoptosis, with chromatin condensation and
fragmentation (30, 31, 32). It is of interest in this context
that overexpression of DNHNF-1 in a rat insulinoma cell line leads
to impaired mitochondrial glucose oxidation and ATP production
(8). Similarly, glucose-induced mitochondrial
hyperpolarization, an essential step in ß-cell activation, is
diminished in a cell line expressing a human HNF-1 mutant
(9). The ultrastructural lesions and the inhibition of
insulin secretion observed in RIP-DNHNF-1 males are thus compatible
with deficient ATP generation by the mitochondria. The resulting
increased ß-cell death could also explain the disorganization of the
islets in transgenic mice.
In conclusion, the results presented here suggest that suppression of
HNF-1 function affects ß-cell metabolism downstream of glucose
transport. Our transgenic mouse model with ß-cell-specific
suppression of HNF-1 function clearly demonstrates that ß-cell
dysfunction must be the primary cause of MODY3. Studies on these
animals should help to further clarify the role of HNF-1 in ß-cell
pathophysiology, and could serve to define HNF-1 target genes in
addition to those described to date (8, 9, 11). Indeed,
because HNF-1 is a transcription factor, it is to be anticipated
that its suppression in the ß-cell changes the expression of as many
genes as was reported recently for the liver (6). The
spectrum of metabolic derangements in the transgenic mice, ranging from
impaired glucose tolerance to frank diabetes, make them ideal for the
development of novel therapeutic strategies for MODY3.
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Acknowledgments |
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antibody. We
also thank Dr. P. Meda, J. Gunn, and F. De Leon for their help. |
Footnotes |
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Abbreviations: DNHNF-1, Dominant-negative mutant of rat
HNF-1; Glut-2; glucose transporter 2; HNF-1, hepatocyte nuclear
factor 1; MODY, maturity-onset diabetes of the young; RIP, rat
insulin promoter.
Received August 2, 2001.
Accepted for publication September 1, 2001.
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References |
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TopAbstractIntroductionMaterials and MethodsResultsDiscussionReferences |
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and 3ß.
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tissue-specific transcriptional targets. Mol Cell Biol 21:3234–3243 is expressed in a hamster insulinoma line and
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